Purine derivatives for the treatment of viral infections

ABSTRACT

The present invention relates to purine derivatives, processes for their preparation, pharmaceutical compositions, and their use in treating viral infections.

CROSS REFERENCE TO RELATED APPLICATION

This application is a divisional application of U.S. patent applicationSer. No. 14/357,495 filed on May 9, 2014 which is a national stage ofPCT Application PCT/EP2012/072090, filed on Nov. 8, 2012, which claimspriority to application EP11188511.7, filed on Nov. 9, 2011, thecomplete disclosures of which are hereby incorporated herein byreference for all purposes.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Jan. 30, 2017, isnamed TIP0258USDIV_SL.txt and is 568 bytes in size.

The current invention relates to purine derivatives, processes for theirpreparation, pharmaceutical compositions, and their use in treatingviral infections.

The present invention relates to the use of purine derivatives in thetreatment of viral infections, immune or inflammatory disorders, wherebythe modulation, or agonism, of toll-like-receptors (TLRs) is involved.Toll-Like Receptors are primary transmembrane proteins characterized byan extracellular leucine rich domain and a cytoplasmic extension thatcontains a conserved region. The innate immune system can recognizepathogen-associated molecular patterns via these TLRs expressed on thecell surface of certain types of immune cells. Recognition of foreignpathogens activates the production of cytokines and upregulation ofco-stimulatory molecules on phagocytes. This leads to the modulation ofT cell behaviour.

It has been estimated that most mammalian species have between ten andfifteen types of Toll-like receptors. Thirteen TLRs (named TLR1 toTLR13) have been identified in humans and mice together, and equivalentforms of many of these have been found in other mammalian species.However, equivalents of certain TLR found in humans are not present inall mammals. For example, a gene coding for a protein analogous to TLR10in humans is present in mice, but appears to have been damaged at somepoint in the past by a retrovirus. On the other hand, mice express TLRs11, 12, and 13, none of which are represented in humans. Other mammalsmay express TLRs which are not found in humans. Other non-mammalianspecies may have TLRs distinct from mammals, as demonstrated by TLR14,which is found in the Takifugu pufferfish. This may complicate theprocess of using experimental animals as models of human innateimmunity.

For a review on toll-like receptors see for instance the followingjournal article: Hoffmann, J. A., Nature, 426, p 33-38, 2003.

Compounds indicating activity on Toll-Like receptors have beenpreviously described such as purine derivatives in WO 2006/117670,adenine derivatives in WO 98/01448 and WO 99/28321, and pyrimidines inWO 2009/067081.

However, there exists a strong need for novel Toll-Like receptormodulators having preferred selectivity, higher potency, highermetabolic stability, higher solubility and an improved safety profilecompared to the compounds of the prior art.

In accordance with the present invention compounds of formula (I) areprovided

or a pharmaceutically acceptable salt, solvate or polymorph thereof,wherein

Y is (C₁₋₄)alkylene,

R₁ is a heteroaryl¹ andR₂ an aryl² or a heterocyclyl.

The term heteroaryl¹ means imidazolyl, pyridyl, pyrimidyl, pyrrolyl,pyrazolyl, furyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazinyl orthiazolyl. Heteroaryl¹ is optionally substituted by one or moresubstituents independently selected from hydroxyl, C₁₋₆ alkyl,C₁₋₄alkoxy, trifluoromethyl, C₃₋₆ cycloalkyl, phenyl, halogen,hydroxyl-C₁₋₄ alkyl, C₁₋₄-alkoxy-C₁₋₄-alkyl-, orC₁₋₄alkyl-diethoxyphosphoryl.

The term aryl² includes phenyl, naphtyl, anthracenyl and phenanthrenyland is preferably phenyl. Aryl² is optionally substituted by one or moresubstituents independently selected from hydroxyl, C₁₋₆ alkyl, C₁₋₄alkoxy, trifluoromethyl, CO₂R₃, R₄R₅N—C₁₋₄-alkyl-, halogen,hydroxyl-C₁₋₄ alkyl-, NR₆R₇, C(O)R₆, C(O)NR₆R₇, C₁₋₄alkyl-diethoxyphosphoryl or C₁₋₄alkyl-phosphonic acid.

R₃ is selected from H and C₁₋₆ alkyl.

R₄ and R₅ taken together with the nitrogen, to which they are bothattached, form a heterocycle selected from the group consisting of:

R₆ and R₇ are each independently selected from H, C₁₋₆-alkyl orC₁₋₄alkoxy.

The term “heterocyclyl” refers to tetrahydropyran and heteroaryl².

The term heteroaryl² includes pyridyl, tetrahydroisoquinolinyl,imidazopyridinyl, quinolinyl, isoquinolinyl, pyrazinyl, pyrimidyl,naphtyridinyl, pyridazinyl, benzimidazolyl, benzothiazolyl, pyrazolyl,thiazolyl, imidazolyl, indazolyl. Heteroaryl² is optionally substitutedby one or more substituents independently selected from halogen,hydroxyl, C₁₋₆ alkyl, C₁₋₄ alkoxy, oxy-C₁₋₄alkylamine orpyrrolidinyl-methanone.

In a further embodiment the current invention encompasses a compound offormula (I) wherein R₁ is selected from the group comprising animidazolyl, a pyrazolyl or a pyridinyl each of which is optionallysubstituted by one or more substituents independently selected fromhalogen, hydroxyl, C₁₋₆ alkyl, C₁₋₄ alkoxy or C₃₋₆ cycloalkyl.

Preferred compounds according to the invention are compounds listed inTable 1 and Table 2 respectively under the heading of the followingnumbers: 1, 4, 9, 23, 24, 25, 26, 35, 36, 48, 49, 50, 51 and 54.

Furthermore to the invention belongs a pharmaceutical compositioncomprising a compound of formula (I) or a pharmaceutically acceptablesalt, solvate or polymorph thereof together with one or morepharmaceutically acceptable excipients, diluents or carriers.

Part of the invention is also a compound of formula (I) or apharmaceutically acceptable salt, solvate or polymorph thereof or apharmaceutical composition above mentioned for use as a medicament.

The invention also related to a compound of formula (I) or apharmaceutically acceptable salt, solvate or polymorph thereof or apharmaceutical composition above mentioned for use in the treatment of adisorder in which the modulation of TLR7 is involved.

The term “alkyl” refers to a straight-chain or branched-chain saturatedaliphatic hydrocarbon containing the specified number of carbon atoms.

The term “halogen” refers to fluorine, chlorine, bromine or iodine.

The term “cycloalkyl” refers to a carbocyclic ring containing thespecified number of carbon atoms.

The term “alkoxy” refers to an alkyl (carbon and hydrogen chain) groupsingular bonded to oxygen like for instance a methoxy group or ethoxygroup.

Pharmaceutically acceptable salts of the compounds of formula (I)include the acid addition and base salts thereof. Suitable acid additionsalts are formed from acids which form non-toxic salts. Suitable basesalts are formed from bases which form non-toxic salts.

The compounds of the invention may also exist in unsolvated and solvatedforms. The term “solvate” is used herein to describe a molecular complexcomprising the compound of the invention and one or morepharmaceutically acceptable solvent molecules, for example, ethanol.

The term “polymorph” refers to the ability of the compound of theinvention to exist in more than one form or crystal structure.

The compounds of the invention can be present in a so-called“tautomer(s)” formation referring to isomers of organic compounds thatreadily interconvert by a chemical reaction called tautomerization. Thisreaction results in the formal migration of a hydrogen atom or proton,accompanied by a switch of a single bond and adjacent double bond.

The compounds of the present invention may be administered ascrystalline or amorphous products. They may be obtained for example assolid plugs, powders, or films by methods such as precipitation,crystallization, freeze drying, spray drying, or evaporative drying.They may be administered alone or in combination with one or more othercompounds of the invention or in combination with one or more otherdrugs. Generally, they will be administered as a formulation inassociation with one or more pharmaceutically acceptable excipients. Theterm “excipient” is used herein to describe any ingredient other thanthe compound(s) of the invention. The choice of excipient dependslargely on factors such as the particular mode of administration, theeffect of the excipient on solubility and stability, and the nature ofthe dosage form.

The compounds of the present invention or any subgroup thereof may beformulated into various pharmaceutical forms for administrationpurposes. As appropriate compositions there may be cited allcompositions usually employed for systemically administering drugs. Toprepare the pharmaceutical compositions of this invention, an effectiveamount of the particular compound, optionally in addition salt form, asthe active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which carrier may take a widevariety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirably inunitary dosage form suitable, for example, for oral, rectal, orpercutaneous administration. For example, in preparing the compositionsin oral dosage form, any of the usual pharmaceutical media may beemployed such as, for example, water, glycols, oils, alcohols and thelike in the case of oral liquid preparations such as suspensions,syrups, elixirs, emulsions, and solutions; or solid carriers such asstarches, sugars, kaolin, diluents, lubricants, binders, disintegratingagents and the like in the case of powders, pills, capsules, andtablets. Because of their ease in administration, tablets and capsulesrepresent the most advantageous oral dosage unit forms, in which casesolid pharmaceutical carriers are obviously employed. Also included aresolid form preparations that can be converted, shortly before use, toliquid forms. In the compositions suitable for percutaneousadministration, the carrier optionally comprises a penetration enhancingagent and/or a suitable wetting agent, optionally combined with suitableadditives of any nature in minor proportions, which additives do notintroduce a significant deleterious effect on the skin. Said additivesmay facilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as aspot-on, as an ointment. The compounds of the present invention may alsobe administered via inhalation or insufflation by means of methods andformulations employed in the art for administration via this way. Thus,in general the compounds of the present invention may be administered tothe lungs in the form of a solution, a suspension or a dry powder.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, suppositories, injectable solutions or suspensions andthe like, and segregated multiples thereof.

Those of skill in the treatment of infectious diseases will be able todetermine the effective amount from the test results presentedhereinafter. In general it is contemplated that an effective dailyamount would be from 0.01 mg/kg to 50 mg/kg body weight, more preferablyfrom 0.1 mg/kg to 10 mg/kg body weight. It may be appropriate toadminister the required dose as two, three, four or more sub-doses atappropriate intervals throughout the day. Said sub-doses may beformulated as unit dosage forms, for example, containing 1 to 1000 mg,and in particular 5 to 200 mg of active ingredient per unit dosage form.

The exact dosage and frequency of administration depends on theparticular compound of formula (I) used, the particular condition beingtreated, the severity of the condition being treated, the age, weightand general physical condition of the particular patient as well asother medication the individual may be taking, as is well known to thoseskilled in the art. Furthermore, it is evident that the effective amountmay be lowered or increased depending on the response of the treatedsubject and/or depending on the evaluation of the physician prescribingthe compounds of the instant invention. The effective amount rangesmentioned above are therefore only guidelines and are not intended tolimit the scope or use of the invention to any extent.

EXPERIMENTAL SECTION Overall Scheme in the Preparation of FinalCompounds (Method 1)

Preparation of Intermediate A-1.

Diaminomaleononitrile (6 g, 55 mmol) and triethylorthoformate (9.2 mL,55 mmol) were combined in 1,4-dioxane (95 mL) and heated underdistillation conditions until 65 mL of 1,4-dioxane/ethanol had beencollected. The reaction mixture was cooled to room temperature and thesolvent evaporated in vacuo. The residue was purified by columnchromatography using a petroleum ether to 25% ethyl acetate in petroleumether gradient to give 5 g of A-1.

Preparation of Intermediate B-1.

Benzylamine (2.86 mL, 26.3 mmol) was added dropwise to a solution of A-1(4.1 g, mmol) and aniline hydrochloride (50 mg) in ethanol (80 mL),stirring at 10° C. The reaction mixture stirred at room temperature for18 hours. The reaction mixture was added dropwise to 1M NaOH (50 mL),stirring at 10° C., and the resultant suspension stirred at roomtemperature for 18 hours. The solid was collected by filtration, washedwith water and dried in vacuo. The title compound was obtained as offwhite solid, B-1 (4 g).

Preparation of Intermediate C-1.

N-bromosuccinimide (4 g, 22 mmol) was added portionwise to a suspensionof B-1 (4 g, 20 mmol) in THF (50 mL) and the reaction mixture stirred atroom temperature for 10 minutes. The solvent was evaporated in vacuo andthe residue extracted from a saturated aqueous solution of NaHCO₃ (50mL) with ethyl acetate (300 mL), dried over Na₂SO₄, the solids wereremoved by filtration, and the solvents of the filtrate were removedunder reduced pressure. The residue was purified via columnchromatography using a dichloromethane to 5% methanol in dichloromethanegradient. The best fractions were pooled, the solvents were removedunder reduced pressure to afford a pink solid, C-1 (3 g).

Preparation of Intermediate D-1.

Trichloroacetonitrile (4.8 g, 17.3 mmol) was added to a suspension ofC-1 (4 g, 14.4 mmol) and Cs₂CO₃ (9.4 g, 29 mmol) in toluene (50 mL) andthe reaction mixture was stirred at room temperature for 48 hours. Themixture was poured into water (100 mL) and extracted with ethyl acetate(3×50 mL), dried over Na₂SO₄, the solids were removed by filtration, andthe filtrate was concentrated in vacuo. The residue was suspended inethanol (20 mL) and stirred at room temperature for 2 hours. Theresultant solid was collected by filtration and washed with methanol toyield an off white solid, D-1 (2.7 g).

Preparation of Intermediate F-1

Sodium methoxide (2.4 g, 0.06 mol) was added to a suspension of D-1 (5g, 12 mmol) in methanol (100 mL) and the reaction mixture was heated atreflux for 16 hours. The mixture was cooled in an ice-water bath andquenched with water. The methanol was evaporated in vacuo and theresidue was extracted with ethyl acetate. The organic layer was driedand concentrated to afford F-1 (4.6 g, crude).

Preparation of Intermediate G-1.

Intermediate F-1 (4.6 g, 15 mmol) was suspended in 6N HCl (aq.)(75 mL)and the reaction mixture was stirred for 32 hours at room temperature.The mixture was neutralized with ammonia and the resultant precipitatewas collected by filtration and washed with water to afford G-1 (3.2 g).

Preparation of Intermediate H-1.

2N NaOH (aq.) was added to a solution of G-1 (1 g, 3.34 mmol) inmethanol (50 mL) and the reaction mixture was stirred at roomtemperature for 2 hours. Methanol was removed under reduced pressure andthe reaction mixture was acidified to pH 2 with 2N HCl (aq). Theresultant precipitate was collected by filtration and washed with waterto afford H-1 (0.95 g).

Preparation of Intermediate I-1.

A mixture of H-1 (500 mg, 1.4 mmol), Aminoketone 2 (284 mg, 1.6 mmol)and EDCl (460 mg, 2.4 mmol) in pyridine (10 mL) was heated in themicrowave to 110 degrees C. for 0.5 hour. The mixture was concentratedto give the crude product which was washed with acetonitrile (10 mL) andcold water to give the intermediate product I-1, as an off-white solid(0.5 g).

Compound 1.

NH₄OAc (5 g) was added to a vial and heated in an oil bath until melted.Then I-1 (100 mg) was added and the reaction mixture was heated in themicrowave for 1 hour at 180° C. The mixture was poured into water andextracted with a mixed organic solvent (dichloromethane: isopropanol3:1, 2×60 mL), dried and concentrated. The crude product was purified bypreparative HPLC to afford a yellow solid, 1 (105 mg).

Compound 2.

Compound 2 was synthesized according to the procedure to synthesizecompound 1 (230 mg).

Compound 3.

Compound 3 was synthesized according to the procedure to synthesizecompound 1 (205 mg).

General Procedure for the Preparation of Aminoketones.

A carboxylic acid (1) is converted to the corresponding acid chloride 2via thionyl chloride. It is also possible to employ other chlorinatingagents, for example oxalyl chloride or phosphorous oxychloride). Theacid chloride (2) is treated with diazomethane at lower temperature toafford a diazoketone (3). Diazoketone (3) is converted to itsalfa-chloroketone (4) via addition of hydrochloric acid at lowtemperature. The chlorine of the alfa-chloroketone (4) is displaced byan azide, from an appropriate azide source like sodium azide, in thepresence of, usually, a dipolar aprotic solvent, for example DMSO.

Preparation of Aminoketone 1.

Step 1.

To a solution of A (15 g, 0.13 mol) in toluene (50 mL) was added SOCl₂(15 mL). The reaction mixture was refluxed for 3 h. Toluene was removedunder reduced pressure. The acid chloride product was obtained as abrown liquid (16 g) and used in the next step directly.

Step 2.

To a solution of B (16 g, 0.12 mol) in diethylether (100 mL) was addedCH₂N₂ (200 mL) at 0° C. The reaction mixture was stirred for 2 h at thistemperature. The ether was removed in vacuo at room temperature. Theproduct was purified by flash chromatography (silica gel, eluent:petroleum ether: ethyl acetate 10:1) to give C (12 g).

¹H NMR (CDCl₃, 400 MHz): δ (ppm) 5.18 (br. s., 1H), 2.65 (br. s., 1H),1.45-1.81 (m, 8H)).

Step 3.

To a solution of C (12 g, 0.096 mol) in THF (65 mL) was added 4NHCl/dioxane dropwise at 0° C. The reaction was monitored by TLC. Thereaction was neutralized with NaHCO₃ (sat. aq.). The mixture wasextracted with ethyl acetate (2×150 mL), dried and concentrated to giveD (11 g). This product was used to next step immediately.

¹H NMR (CDCl₃, 400 MHz): δ (ppm) 4.10 (s, 2H), 3.04 (quin, J=7.3 Hz,1H), 1.54-1.87 (m, 8H)

Step 4.

To a solution of D (7.3 g, 0.05 mol) in DMSO (30 mL) was added NaN₃ (3.9g, 0.06 mol). The reaction was stirred for overnight and monitored byTLC. The reaction was poured into water (50 mL) and extracted with ethylacetate (2×100 mL), dried over sodium sulfate, the solids were removedby filtration and the solvents of the filtrate were removed underreduced pressure. The crude product was purified by silica gelchromatography using a petroleum ether to ethyl acetate gradient toafford E (5.28 g).

¹H NMR (CDCl₃, 400 MHz): δ (ppm) 3.93 (s, 2H), 2.83 (quin, J=7.3 Hz,1H), 1.56-1.84 (m, 8H)

Step 5.

A mixture of E (3.28 g, 0.02 mol), conc. HCl (1.8 mL, 0.02 mol) and 1 gPd/C (10%) in 30 mL of methanol was stirred for overnight under 50 psiof hydrogen atmosphere. The reaction mixture was filtered andconcentrated to give Aminoketone-1 (2 g).

¹H NMR (MeOD, 400 MHz): δ (ppm) 4.03 (s, 2H), 3.01-3.12 (quin, J=7.3 Hz,1H), 1.67-1.98 (m, 8H)

Aminoketone-2

Aminoketone-2 was prepared according to the procedure to prepareAminoketone-1.

Aminoketone 3

Aminoketone-3 was prepared according to the procedure to prepareAminoketone-1.

Overall Scheme in the Preparation of Final Products (Method 2)

Preparation of Compound 4:

A mixture of C-1 (1.6 g, 5.78 mmol) (its synthesis as such is describedin WO20060117670 on pages 59-60: “Preparation 6, 7 and 8” respectivelyto obtain Amino-1-benzyl-2-bromo-1H-imidazole-4-carbonitrile) and2-cyano-imidazole (592 mg, 6.35 mmol) in NH₃/MeOH (7N) (60 mL) werestirred at 140° C. for 48 hours in a pressure vessel reactor. Thesolvent was evaporated. The crude compound was purified by columnchromatography over silica gel column (15-40 μm, 40 g), inDCM/MeOH/NH₄OH 97/3/0.5→95/5/0.5) to give compound 4 (78 mg, 4.4%yield).

Alternative Synthesis of Compound 1:

Step 1:

EtONa (904 mg; 13.3 mmol) was added to a solution of 2-cyano-imidazoleI-1 (0.7 g; 2.66 mmol) and intermediate C-1 (736 mg; 2.66 mmol) in EtOH(30 mL). The mixture was stirred at 90° C. for 16 h. The solvent wasremoved under reduced pressure. The crude was purified by preparative LC(irregular SiOH 45 g Merck, mobile phase 97/3/0.1 to 95/5/0.5) to give0.51 g of the SEM-protected ethoxy intermediate as a lightly yellowsolid (38% yield).

HPLC Rt (min)=7.45; MS M+ (H⁺): 506 method (v2003v2002)

Step 2:

NaF (170 mg; 4.05 mmol) was added to a solution of SEM-protected ethoxyintermediate (0.41 g; 0.811 mmol) in THF (28 mL), HCl (37% in H₂O) (28mL) and MeOH (10 mL). The mixture was stirred at 40° C. for 16 h. Themixture was cooled to RT and a 10% solution of K₂CO₃ was added until thepH of the solution was basic. The aqueous layer was saturated with K₂CO₃powder and the product was extracted with DCM/MeOH (5%) (3 times). Thecombined organic layers were dried over MgSO₄, filtered and the solventwas removed under reduced pressure. The crude was purified bypreparative LC (irregular SiOH 15-40 μm, mobile phase DCM/MeOH/NH₃aq95/5/0.5 to 90/10/0.5) to give 120 mg of compound 1 as a white powder(43% yield).

Synthesis of the 2-Cyano-Imidazole Intermediates: Synthesis ofIntermediate J-1:

NaCN (360 mg; 7.35 mmol) was added to a suspension ofcyclopropane-carboxaldehyde (5 g; 71.3 mmol) and tosylmethyl-isocyanide(13.7 g; 69.9 mmol) in EtOH (200 mL). The resulting mixture was stirredfor 1 h at RT. The solvent was removed under reduced pressure and theresidue was washed with a mixture of heptane/ether (1:1). The beigedried powder was stirred in NH₃/MeOH 7N (480 mL; 3.36 mol) and themixture was stirred at 100° C. in steel bomb for 16 h. The mixture wascooled to RT and the solvent was evaporated under reduced pressure.iPr₂O was added to the residue and the solid was filtered. The filtratewas evaporated to dryness and the crude was purified by preparative LCon (Irregular SiOH 20-45 μm 1000 g DAVISIL). Mobile phase (0.5% NH₄OH,94% DCM, 6% MeOH). The pure fraction was collected and evaporated togive 4.9 g of intermediate J-1a as a brown oil (65% yield).

¹H NMR (DMSO-d₆, 400 MHz): δ (ppm) 8.60 (br. s., 1H), 7.58 (s, 1H), 6.76(s, 1H), 1.85 (m, 1H), 0.86 (m, 2H), 0.71 (m, 2H).

J-1a (4.84 g; 44.8 mmol) in THF (60 mL) was added dropwise to asuspension of NaH (1.97 g; 49.2 mmol) in THF (200 mL) at 0° C. under N₂.The mixture was stirred at RT for 30 min and SEM-CI (9.9 mL; 55.9 mmol)in THF (20 mL) was added dropwise at 0° C. The mixture was stirred at RTunder N₂ for 16 h. Water was added and the product was extracted withDCM. The organic layer was dried over MgSO₄, filtered and concentratedunder reduced pressure. The crude was purified by preparative LC(Irregular SiOH 20-45 μm, 150 g Merck, Mobile phase Gradient from 50%DCM, 50% heptane to 100% DCM). The fractions containing pure compoundwere combined and the solvent was removed under reduced pressure to give6.6 g of J-1b as a yellow oil (62%).

Mixture of 2 regioisomers: 70/30

Minoritory Regioisomer:

¹H NMR (DMSO-d₆, 400 MHz): δ□(ppm) 7.64 (s, 1H), 6.56 (s, 1H), 5.34 (s,1H), 3.45 (t, J=8.08 Hz, 2H), 1.73-1.78 (m, 1H), 0.80-0.86 (m, 2H),0.72-0.74 (m, 2H), 0.52-0.57 (m, 2H), −0.04 (s, 9H).

Majoritory Regioisomer:

¹H NMR (DMSO-d₆, 400 MHz): δ□(ppm) 7.56 (s, 1H), 6.94 (s, 1H), 5.20 (s,1H), 3.43 (t, J=8.08 Hz, 2H), 1.73-1.78 (m, 1H), 0.80-0.86 (m, 2H),0.72-0.74 (m, 2H), 0.56-0.62 (m, 2H), −0.04 (s, 9H).

BrCN (6.11 g; 57.7 mmol) was added to a solution of DMAP (7.05 g; 57.7mmol) in DMF (60 mL) at 10° C. The reaction was exothermic to 35° C. anda pale yellow precipitate was formed. The mixture was cooled to 10° C.and J-1b (5.5 g; 23.1 mmol) was added. The mixture was stirred at 40° C.for 6 h. Water was added and product was extracted with Et₂O (2 times).The combined organic layers were washed with brine, dried over MgSO₄,filtered and the solvent was removed under reduced pressure.

The crude was purified by preparative LC (Irregular SiOH 15-40 μm 220 ggrace, mobile phase Heptane/DCM 50/50 to 10/90) to give 2.2 g impureJ-1, which was further purified by preparative LC (irregular SiOH 15-40μm 90 g Merck, mobile phase heptane/DCM 30/70) to give 0.94 g of J-1 asa mixture of two region-isomers (15% yield).

HPLC Rt (min)=6.11; MS M+ (H⁺): 264 (method V1004V1012) Alternativesynthesis of intermediate J-1:

BuLi (1.6M in hexane)(11 mL; 17.6 mmol) was added to a solution of J-1b(3.5 g; 14.7 mmol) in THF (60 mL) at −50° C. The mixture was stirred atthe same temperature for 30 min and DMF (1.7 mL; 22 mmol) was added. Themixture was warmed slowly to RT in 1 h and NH₂OH, HCl (970 mg; 29.4mmol) was added and the mixture was stirred at RT for 16 h. Water wasadded and the product was extracted with DCM (3 times), washed withbrine, dried over MgSO₄ and the solvent was removed under reducedpressure to give 4.1 g (quantitative yield) of the mixture of isomersK-1 as yellow oil.

HPLC Rt (min)=5.30, 5.41 and 5.90; MS M+ (H⁺): 282 (method V2002V2002)

K-1 (3.1 g; 11 mmol) was dissolved in DCM (18 mL) and pyridine (19 mL)at RT. The mixture was cooled to 0° C. and TFAA (4.6 mL; 33 mmol) wasadded. The mixture was stirred at RT for 24 h. The solvent was removedunder reduced pressure and the residue was dissolved in AcOEt. Theorganic layer was washed with water and brine, dried over MgSO₄,filtered and the solvent was removed under reduced pressure. The crudewas purified by preparative LC (irregular SiOH 15-40 μm 90 g merck,mobile phase Heptane/DCM 30/70 to DCM 100%) to give 2.14 g ofintermediate J-1 (73%) as a mixture of two isomers.

HPLC Rt (min)=6.51; MS M+ (H⁺): 264 (method V2002V2002)

Overall Scheme in the Preparation of Final Products: (Method 3)

Synthesis of Intermediate N-1.

In a CEM microwave oven, a mixture of M-1 (its synthesis as such isdescribed in WO2006117670 pages 57-58 “Preparation 1-4” respectively toobtain 6-Amino-9-benzyl-2-chloro-7,9-dihydro-purin-8-one) (9.7 g, 37.351mmol), NaCN (3.11 g, 63.50 mmol) in DMSO (100 mL) was stirred at 150° C.for 4 h. The mixture was poured into water and the precipitate wasfiltered off, washed with water and dried under vacuum at 60° C. to give8.6 g of intermediate N-1.

HPLC Rt (min)=5.23; MS M+ (H⁺): 251 (method V2003V2002)

Synthesis of Intermediate O-1.

FeCl₃ (tip spatula) was added to a mixture of N-1 (3.70 g, 147.84 mmol)and NBS (26.2 g, 147.845 mmol) in CHCl₃ (60 mL). The mixture was stirredand refluxed for 3 h and then cooled to RT. The precipitate was filteredoff. The filtrate was evaporated and purified by flash chromatographyover silica gel (15-40 μm, 120 g, CH₂Cl₂/CH₃OH 99-1) to give 4.5 g ofimpure intermediate O-1. The fraction was taken up CH₂Cl₂ and theprecipitate was filtered off to give 1.8 g of intermediate O-1.

HPLC Rt (min)=5.77; MS M+ (HCH₃CN⁺): 370-372 (method V2003V2002)

Synthesis of Intermediate P-1.

A mixture of O-1 (0.82 g, 2.491 mmol), MeONa/MeOH (30 wt % solution)(1.15 mL, 6.228 mmol) in MeOH (15 mL) was stirred at 50° C. for 2 h.NH₄Cl (333 mg, 6.228 mmol) was added and the mixture was stirred andrefluxed for 2 h. The solvent was evaporated under reduced pressure. Thecrude was purified by flash chromatography over silica gel (15-40 μm, 90g, CH₂Cl₂/CH₃OH/NH₄OH: 85-14-1). The pure fractions were collected andconcentrated under reduced pressure to give 0.55 g of intermediate P-1(74% yield).

HPLC Rt (min)=4.46; MS M+ (H⁺): 298 (method V2003V2002)

Synthesis of Intermediate Q-1.

2-bromo-1-cyclopropyl-propan-1-one (104 mg, 0.589 mmol) was addeddropwise to a mixture of P-1 (175 mg, 0.589 mmol) and DBU (0.264 mL,1.766 mmol) in EtOH (5 mL). The mixture was stirred and refluxed for 5h. The solvent was concentrated under reduced pressure. The crude waspurified by flash chromatography over silica gel (15-40 μm, 40 g,CH₂Cl₂/CH₃OH/NH₄OH:95/5/0.1). The pure fractions were collected andconcentrated under reduced pressure to give 40 mg of intermediate Q-1.The crude compound was used directly in the next step.

HPLC Rt (min)=5.35; MS M+ (H⁺): 376 (method V1005V1012)

Synthesis of Final Compound 5:

A mixture of Q-1 (40 mg, 0.107 mmol) in HCl 6N (1 mL) and dioxane (1 mL)was stirred at RT for 6 h. The mixture was half-evaporated under reducepressure. The solution was cooled to 0° C., basified with NaHCO₃ andextracted with EtOAc-CH₃OH (90-10). The combined organic layers weredried over MgSO₄, filtered and the solvent was evaporated under reducepressure. The crude was purified by flash chromatography over silica gel(15-40 μm, 10 g, CH₂Cl₂/CH₃OH/NH₄OH:88-12-0.5) The pure fractions werecollected and concentrated under reduced pressure. The resulting solid(35 mg) was crystallized from Et₂O to afford 25 mg of Compound 5 (64%yield, MP >260° C.).

Overall Scheme in the Preparation of Final Products: (Method 4)

Synthesis of Intermediate T-1:

S-1 (synthesis described in J. Med. Chem. 1996, 39, 13, 2586-2593) (1.14g; 9.33 mmol) was added drop wise to a solution of R-1 (synthesisdescribed in WO2006/117670) (1.46 g; 8.89 mmol) and aniline, HCl (18 mg;0.14 mmol) in EtOH (30 mL) at 10° C. The reaction mixture was stirred atRT for 20 h. An aqueous solution of NaOH 3M (30 mL) was added dropwiseto the solution at 10° C. and the resultant mixture was stirred at RTfor 1 h. The aqueous layer was extracted with DCM (3 times). Thecombined organic layers were washed with a saturated aqueous solution ofNaHCO₃, dried over MgSO₄, filtered and concentrated in vacuo to give1.20 g of T-1 as a brown solid (63% yield). T-1 was used in the nextstep without further purification.

HPLC Rt (min)=4.45; MS M+ (H⁺): 214 (method V1010V1012)

Synthesis of Intermediate U-1:

A solution of NCS (475 mg; 3.56 mmol) in THF (10 mL) was added dropwiseto a solution of T-1 (690 mg; 3.24 mmol) in THF (35 mL). The solutionwas stirred at RT for 20 h under N₂ flow. A solution of NCS (260 mg;1.94 mmol) in THF (5 mL) was added drop wise to the solution. Thesolution was stirred at RT for 16 h under N₂ flow. The mixture was takenup with DCM, washed with a saturated aqueous solution of NaHCO₃, washedwith brine, dried over MgSO₄, filtered and evaporated in vacuo to give950 mg of a brown solid. The crude was purified by preparative LC(Irregular SiOH 15-40 μm, 40 g Grace, liquid sample, mobile phase: 98%DCM, 2% MeOH to 90% DCM, 10% MeOH). The fractions containing purecompound were combined and the solvent was removed in vacuum to give 200mg of U-1 as a brown solid (25% yield).

HPLC Rt (min)=5.13; MS M+ (H⁺): 248-250 (method V2012V2002)

Synthesis of Intermediate W-1:

EtONa (398 mg; 5.85 mmol) was added to a solution of U-1 (290 mg; 1.17mmol) and V-1 (270 mg; 1.21 mmol) in EtOH (15 mL). The mixture wasstirred at 90° C. for 16 h. The solvent was removed under reducedpressure. The crude was purified by preparative LC (irregular SiOH 15-40μm, 50 g Merck, solid sample, mobile phase 97/3/0.1). The fractioncontaining pure compound were combined and the solvent was removed togive 210 mg of W-1 as a lightly yellow solid (37% yield).

HPLC Rt (min)=6.68; MS M+ (H⁺): 248-250 (method V1010V1012)

Synthesis of Compound 9:

NaF (91 mg; 2.18 mmol) was added to a solution of W-1 (210 mg; 0.44mmol) in HCl 37% in water (15 mL) and MeOH (10 mL). The mixture wasstirred at 40° C. for 16 h. The mixture was cooled to RT and a 10%aqueous solution of K₂CO₃ was added until basic pH. The aqueous layerwas saturated with K₂CO₃ powder and the product was extracted withDCM/MeOH (95/5) (3 times). The combined organic layers were dried overMgSO₄, filtered and the solvent was removed under reduced pressure. Thecrude was purified by preparative LC (irregular SiOH 15-40 μm, Merck 10g, mobile phase DCM/MeOH/NH₃aq 93/3/0.1 to 85/15/1). The fractionscontaining pure compound were combined, the solvent was removed in vacuoand the title compound was dried in vacuo for 16 h at 60° C. to give 9.8mg of Compound 9 (6%) as a pale brown solid. m.p. >260° C.

Overall Scheme in the Preparation of Final Products: (Method 5)

Synthesis of Intermediate Y1:

Sodium methoxide (30 wt % in MeOH) (15.6 mL, 84.172 mmol) was added dropwise to a mixture of X1 (synthesis described in Bioorg. Med. Chem., 11,2003, 5501-5508) (5.7 g, 16.834 mmol) in MeOH (150 mL) at RT. Themixture was stirred at 60° C. for 6 h and then cooled down to RT. Theprecipitate was filtered off and dried, to yield 3.25 g of Y1. The crudecompound was used in the next step.

HPLC Rt (min)=5.53; MS M+ (H⁺): 290-292 (method V2003V2002)

Synthesis of Intermediate Z-1:

Boc₂O (3.0 g, 13.806 mmol) was added under a N₂ flow to a mixture of Y-1(1.0 g, 3.452 mmol), DMAP (42 mg, 0.345 mmol) in THF (10 mL) at RT. Themixture was stirred at 80° C. for 2 h. The mixture was poured into waterand extracted with EtOAc. The organic layer was washed with water, driedover MgSO₄, filtered and the solvent was evaporated. The crude waspurified by preparative LC on (Irregular SiOH 20-45 μm 450 g MATREX).Mobile phase (Gradient from 98% DCM, 2% AcOEt to 95% DCM, 5% AcOEt) toafford 0.825 g of Z-1 (49% yield, MP=159° C.).

HPLC Rt (min)=4.43; MS M+ (H⁺): 490-492 (method V2015V2007)

Synthesis of Intermediate B-2:

A solution of Z-1 (300 mg, 0.612 mmol), A-2 (255 mg, 0.918 mmol) andNaHCO₃ (257 mg, 3.06 mmol) in dioxane/water (4/1) (3 mL) was degassed bybubbling N₂ for 10 min. Tetrakis-(triphenylphosphine)-Palladium (142 mg,0.122 mmol) was added and the mixture was stirred at 100° C. for 5 h.Water and EtOAc were added and the layers were decanted. The aqueouslayer was extracted with EtOAc. The organic layers were combined, driedover MgSO₄, filtered and the solvent was evaporated in the next stepwithout further purification.

Synthesis of Final Compound 23:

HCl 6N (10 mL) was added to a solution of B-2 (0.7 g, 1.15 mmol) indioxane (7 mL) at 0° C. The mixture was stirred at RT for 12 h and thencooled down to 0° C. and basified with K₂CO₃. The mixture was extractedwith EtOAc+CH₃OH (90-10). The combined organic layers was dried overMgSO₄, filtered and the solvent was evaporated. The crude was purifiedby preparative LC on (Stability Silica 5 μm 150×30.0 mm). Mobile phase(Gradient from 0.3% NH4OH, 97% DCM, 3% MeOH to 1.4% NH4OH, 86% DCM, 14%MeOH), to yield 67 mg of final Compound 23 after crystallization fromCH₃OH (19% yield).

Overall Scheme in the Preparation of Final Products: (Method 6)

Synthesis of Intermediate C-2:

A mixture of Y-1 (0.53 g, 1.829 mmol) in HCl 6N (5 mL) and dioxane (5mL) was stirred at RT for 18 h. The precipitate was filtered off, washedwith the minimum of cold dioxane and dried to afford 0.28 g of crudeC-2, which was used in the next step without further purification.

HPLC Rt (min)=4.96; MS M+ (H⁺): 276-278 (method V2003V2002)

Synthesis of Intermediate D-2:

NEt₃ (0.187 mL, 1.345 mmol) and then Boc₂O (0.215 g, 0.987 mmol) wereadded to a mixture of C-2 (0.28 g, 0.897 mmol) and DMAP (11 mg, 0.0897mmol) in THF (3 mL) at RT. The mixture was stirred at 80° C. for 2 h.Water and EtOAc were added. The layers were decanted. The organic layerwas dried over MgSO₄, filtered and the solvent was evaporated to yield0.18 g of intermediate D-2. The crude compound was used directly in thenext step.

HPLC Rt (min)=6.31; MS M+ (H⁺): 376-378 (method V2002V2002)

Synthesis of Final Compound 20:

A solution of D-2 (240 mg, 0.64 mmol), E-2 (107 mg, 0.96 mmol) andNaHCO₃ (269 mg, 3.2 mmol) in dioxane/water (4/1) (3.2 mL) was degassedby bubbling N₂ for 10 min. Tetrakis-(triphenylphosphine)-Palladium (148mg, 0.13 mmol) was added and the mixture was stirred at 100° C. for 16h. Water and EtOAc were added and the layers were decanted. The aqueouslayer was extracted with EtOAc. The organic layers were combined, driedover MgSO₄, filtered and the solvent was evaporated. The crude waspurified on a reverse phase to yield 13 mg of final Compound 20 (6%yield).

Overall Scheme in the Preparation of Final Products: (Method 7)

Synthesis of Final Compound 36:

A mixture of Z-1 (300 mg, 0.612 mmol) and pyrazole (417 mg, 6.123 mmol)was stirred at 180° C. for 1 h (microwave biotage). The crude compoundwas purified by chromatography over silicagel column (15-40 μm, 25 g) inCH₂Cl₂/MeOH/NH₄OH 96/4/0.5 to give, after crystallization indiisopropylether and drying under vacuum pressure at 80° C., 85 mg offinal compound 36.

Overall Scheme in the Preparation of Final Products: (Method 8)Synthesis of Intermediate G-2:

A solution of F-2 (50 g, 316.09 mmol) in TFA (210 mL) was stirred at RTfor 30 min. The mixture was cooled to 5° C. then HNO₃ fuming (19.5 mL,426.73 mmol) was added drop wise at 5° C. The temperature was maintainedat 10-15° C. during the addition.

The ice bath was removed and when the temperature reached 20° C., aviolent exothermic event occurred (from 20° C. to 45° C. in 5 seconds).The mixture was stirred at RT for 16 h. The mixture was poured into amixture of water and ice. The precipitate was filtered off and washedwith water. The precipitate was dried under vacuum at 50° C. to give 42g (65% yield) of intermediate G-2. This intermediate was directly usedin the next step without any further purification.

Synthesis of Intermediate H-2:

N,N-dimethylaniline (76.7 mL, 0.61 mol) was added drop wise to POCl₃(93.7 mL, 1.01 mol) at 0° C. G-2 (41 g, 201.79 mmol) was added portionwise at 0° C. then the mixture was warmed to 100° C. for 2 h. Thesolution was concentrated under vacuum and the residual POCl₃ wasremoved by azeotropic evaporation with toluene (3 times). The resultingoil was taken up in a solution of CH₂Cl₂-Heptane (70-30) and wasfiltered through a glass filter of SiO₂. The filtrate was concentratedand the residue was purified by preparative LC on (Irregular SiOH 20-45μm 1000 g DAVISIL), mobile phase (80% Heptane, 20% CH₂Cl₂). The purefractions were collected and concentrated to give 37.8 g (78% yield) ofintermediate H-2.

Synthesis of Intermediate I-2:

A solution of NH₃ 2M in iPrOH (115 mL, 229.31 mmol) was added drop wiseto a solution of H-2 (36.7 g, 152.87 mmol) and Et₃N (23.4 mL, 168.16mmol) in THF (360 mL) (the temperature was maintained at RT with anice-water bath during the addition). The reaction mixture was stirred atRT for 5 h. The mixture was evaporated to dryness. Water and EtOAc wereadded to the residue. The layers were separated and the aqueous layerwas extracted with EtOAc (twice). The combined organic layers were driedover MgSO₄, filtered, and the solvent was removed under reduced pressureto give 34.5 g (100% yield) of intermediate 1-2.

Synthesis of Intermediate J-2:

Ethyl chloroformate (13.5 mL, 138.90 mmol) was added to a solution of1-2 (39.8 g, 126.27 mmol) and Et₃N (26.5 mL, 189.40 mmol) in THF (1300mL). The mixture was stirred at RT for 6 h and the solvent was partiallyevaporated under reduced pressure. The residue was taken up in CH₂Cl₂and water. The layers were separated; the aqueous layer was extractedwith CH₂Cl₂ (twice). The combined organic layers were dried over MgSO₄,filtered and the solvent was removed under reduced pressure. The residuewas purified by preparative LC on (Irregular SiOH 20-45 μm 1000 gDAVISIL), mobile phase (gradient from 85% heptane, 15% AcOEt to 80%heptane, 20% AcOEt). The pure fractions were collected and concentratedto give 35 g (95% yield) of intermediate J-2.

Synthesis of Intermediate L-2:

J-2 (5 g, 17.0 mmol), K-2 (3.91 g, 17.0 mmol), K₂CO₃ (5.90 g, 42.7 mmol)and NaI (2.56 g, 17.0 mmol) in acetone (130 mL) were stirred at RT for18 h. The solution was filtered and the filtrate was evaporated underreduced pressure. The crude compound was purified by preparative LC(irregular SiOH 15-40 μm, 120 g merck, solid sample, mobile phase:heptane/EtOAc 100/0 to 80/20) to give intermediate L-2 as a pale yellowsolid (69% yield).

Synthesis of Intermediate M-2:

The reaction was done in two batches of 2.7 g of L-2.

Here is the protocol for one batch of 2.7 g: In a sealed tube, L-2 (2.70g, 6.12 mmol) was stirred in NH₃ (7 M in MeOH) (50 mL) and THF (50 mL)at RT for 2 h.

The two batches were mixed.

The mixture was evaporated in vacuo and the residue was dried byazeotropic distillation with EtOH (twice) to give a yellow solid. Waterand EtOAc were added, the layers were separated and the aqueous layerwas extracted with EtOAc (twice). The combined organic layers were driedover MgSO₄, filtered and evaporated in vacuo to give 4.9 g ofintermediate M-2 as a yellow solid (90% yield).

Synthesis of Intermediate N-2:

mCPBA (1.46 g, 5.93 mmol) was added portionwise to a solution of M-2 (1g, 2.37 mmol) in CH₂Cl₂ (60 mL) at 0° C. The mixture was stirred at RTfor 20 h. An aqueous solution of Na₂S₂O₃ was added to the mixture. Thelayers were separated and the aqueous layer was extracted with CH₂Cl₂(twice). The combined organic layers were washed with a saturatedaqueous solution of NaHCO₃, dried over MgSO₄, filtered and the solventwas removed under reduced pressure to give 980 mg of intermediate N-2 asa yellow solid (91% yield). Intermediate N-2 was used in the next stepwithout further purification.

Synthesis of Intermediate O-2:

A mixture of N-2 (500 mg, 1.10 mmol) and pyrazole (750 mg, 11.0 mmol)was stirred at 80° C. for 45 min. The resulting mixture was take up withEtOAc and 1 M aqueous solution of HCl. The layers were separated, theorganic layer was dried over MgSO₄, filtered and dried in vacuo to give550 mg of a yellow solid. The crude compound was purified by preparativeLC (irregular SiOH 15-40 μm, 25 g Grace, solid sample, mobile phasegradient: from CH₂Cl₂/MeOH/NH₃aq 97/3/0.03 to 80/20/0.3) to give 370 mgof intermediate O-2 as a white solid (76% yield).

Synthesis of Final Compound 37:

Fe (280 mg, 5.01 mmol) was added to a mixture of O-2 (365 mg, 827 μmol)in AcOH (17 mL) and water (1.8 mL). The mixture was stirred vigorouslyat RT for 64 h. The reaction mixture was filtered on a pad of celite,concentrated in vacuo and co-evaporated with toluene (twice) to give adark residue. The crude was purified by preparative LC (Irregular SiOH15-40 μm, 25 g Merck, solid sample, mobile phase gradient: fromCH₂Cl₂/MeOH/NH₃aq 96/4/0.4 to 80/20/3) to give 250 mg of a white solid,which was purified again by preparative LC (Irregular SiOH 15-40 μm, 25g Merck, solid sample, mobile phase gradient: from CH₂Cl₂/MeOH/NH₃aq96/4/0.4 to 80/20/3) to give 110 mg of fraction 1 as a white solid (36%)and 25 mg of fraction 2 as a white solid (8%). Global yield: 45%. 8 mgof fraction 2 were dried in vacuo for 16 h at 40° C. to give 6 mg offinal compound 37 as a white solid.

Synthesis of Final Compound 38:

LiOH (9 mg, 123 μmol) was added to a suspension of 37 (15 mg, 41.1 μmol)in THF (4 mL) and water (5 mL). The reaction mixture was stirred at RTfor 16 h. A 10% aqueous solution of K₂CO₃ was added until basic pH. Theaqueous layer was saturated with K₂CO₃ powder and the product wasextracted with CH₂Cl₂/MeOH (9/1) (3 times). The combined organic layerswere dried over MgSO₄, filtered and the solvent was removed underreduced pressure to give 200 mg. The crude was purified by preparativeLC on (X-Bridge-C18 5 μm 30*150 mm, mobile phase: gradient H₂O (0.1%Formic Acid)/MeCN 90/10 to 0/100) to give 12 mg of final compound 38 asa white solid (83%).

Synthesis of Final Compound 39:

Dibal-H (1.2 M in toluene) (0.2 mL, 240 μmol) was added dropwise to asolution of 37 (30 mg, 82.1 μmol) in THF (3 mL) and toluene (1 mL) undernitrogen at 0° C. The solution was stirred at 0° C. for 2 h. Dibal-H(0.2 mL, 240 μmol) was added and the solution was stirred at RT for 2 h.A saturated aqueous solution of potassium sodium tartrate was added toneutralize the reaction. The mixture was diluted with EtOAc, followed bystirring vigorously for 30 min. The organic layer was separated from theaqueous layer, washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo to give 40 mg. The crude was purified bypreparative LC (irregular SiOH 15-40 μm, 4 g Grace, solid sample, mobilephase gradient: from CH₂Cl₂/MeOH/NH₃aq 96/4/0.04 to 80/20/2) to give awhite solid. The afforded white solid was dried in vacuo for 16 h at 40°C. to give 8 mg of final compound 39 (29%) as a white solid.

Synthesis of Final Compound 40:

39 (45 mg, 133 μmol) was solubilized in HBr (30% in AcOH) (10 mL). Themixture was stirred at RT for 1 h. The solvent was evaporated and AcOHwas azeotropically distilled with toluene (twice) to give 75 mg ofintermediate P-2 as a brown solid, which was used for the next stepwithout further purification.

To a suspension of NaH (53 mg, 1.33 mmol) in THF (4 mL) was addeddropwise diethyl phosphite (0.130 mL, 1.33 mmol) at RT. The mixture wasstirred at RT for 1 h. To the mixture was added a solution of P-2 (64mg, 133 μmol) in THF (4 mL). The mixture was stirred at RT for 16 h. Toa suspension of NaH (53 mg, 1.33 mmol) in THF (4 mL) was added dropwisediethyl phosphite (0.130 mL; 1.33 mmol) at RT. The resulting mixture wasadded to the reaction mixture. The resulting reaction mixture wasstirred at RT for 1 h. Water and EtOAc were added, the layers wereseparated and the organic layer was washed with an aqueous solution ofNaHCO₃ and brine, dried over MgSO₄, filtered and concentrated in vacuoto give 75 mg of a clear oil. The crude was purified by preparative LC(Irregular SiOH 15-40 μm, 25 g Merck, dry loading, mobile phasegradient: from CH₂Cl₂/MeOH 100/0 to 85/15) to give 38 mg of a whitesolid, which was triturated in pentane. The resulting solid was filteredand dried in vacuo for 16 h at 50° C. to give 28 mg of final compound 40as a white solid (40% yield).

Synthesis of Final Compound 41:

40 (590 mg, 1.29 mmol) was solubilized in HCl (37% in water) (60 mL).The mixture was stirred at 100° C. for 16 h. The solvent was evaporatedand H₂O was azeotropically distilled with EtOH (twice) to give 605 mg offinal compound 41 as a white solid (100% yield).

TABLE 1 Compounds of formula (I). LCMS Mass Ret Exact Found Time,Synthesis MP # STRUCTURE Mass [M + H] Method method (° C.) H NMR 1

347.15 348 1.01, B 1, 2 ¹H NMR (600 MHz, DMSO-d₆) δ □ppm 0.84 (br. s., 2H), 0.99 (d, J = 6.7 Hz, 2 H), 2.00 (br. s., 1 H), 3.16 (br. s., 1 H),5.03 (br. s., 2 H), 7.08-7.21 (m, 2 H), 7.24-7.35 (m, 3 H), 7.36-7.45(m, 3 H), 11.51 (br. s., 1 H) 2

383.15 384 1.18, B 1 ¹H NMR (400 MHz, DMSO-d₆) δ □ppm 5.08 (s, 2 H),7.04 (br. s., 2 H), 7.29 (m, J = 7.3 Hz, 1 H), 7.34 (t, J = 7.3 Hz, 2H), 7.40-7.48 (m, 3 H), 7.49-7.56 (m, 2 H), 7.97 (d, J = 7.3 Hz, 2 H),8.20 (s, 1 H), 11.28 (s, 1 H) 3

375.18 376 1 ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 14.45 (br. s., 1H), 11.49(s, 1H), 7.54 (s, 1H), 7.41 (d, J = 8 Hz, 2H), 7.31 (t, J = 8 Hz, 2H),7.28 (t, J = 8 Hz, 1H), 7.14 (br. s., 2H), 5.06 (s, 2H), 3.15 (m, 1H),2.08- 2.06 (m, 2H), 1.74- 1.62 (m, 6H) 4

307.12 308 1.87, V3018V3001 2 >260 ¹H NMR (DMSO-d₆, 400 MHz): δ ppm12.34 (br. s., 1H), 10.32 (br. s., 1H), 7.22-7.44 (m, 5H), 7.18 (s, 1H),7.01 (s, 1H), 6.48 (br. s., 2H), 5.00 (s, 2H) 5

361.16 362 2.35, V3018V3001 3 >260 ¹H NMR (DMSO-d₆, 500 MHz): δ ppm11.89 (br. s., 1H), 10.24 (br. s., 1H), 7.21-7.40 (m, 5H), 6.51 (br. s.,2H), 5.01 (s, 2H), 2.24 (s, 3H), 1.72-1.80 (m, 1H), 0.65-0.78 (m, 4H) 6

375.18 376 2.52, V3018V3001 3 >260 ¹H NMR (DMSO-d₆, 500 MHz): δ ppm11.85 (br. s., 1H), 10.26 (s, 1H), 7.21- 7.39 (m, 5H), 6.51 (br. s.,2H), 5.02 (s, 2H), 2.65 (m, 2H), 1.78 (br. s., 1H), 1.17 (t, J = 6.5 Hz,3H), 0.65-0.78 (m, 4H) 7

335.15 336 2.1,  V3018V3001 3 230 ¹H NMR (DMSO-d₆, 500 MHz): δ ppm 11.98(br. s., 1H), 10.27 (s, 1H), 7.20- 7.40 (m, 5H), 6.40 (s, 2H), 5.01 (s,2H), 2.10 (br. s., 6H) 8

321.13 322 2.01, V3018V3001 3 ¹H NMR (500 MHz, DMSO-d₆) δ ppm12.00-12.17 (m, 1H), 10.29 (s, 1H), 7.35-7.40 (m, 2H), 7.32 (t, J = 7.41Hz, 2H), 7.23-7.29 (m, 1H), 6.66-6.90 (m, 1H), 6.44 (br. s., 2H), 5.00(br. s., 2H), 2.10- 2.26 (m, 3H). 9

322.13 323 2.47, V3018V3001 4 >260 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.38(br. s., 1H), 8.56 (br. s., 1H), 7.71 (d, J = 7.07 Hz, 1H), 7.09-7.30(m, 4H), 6.45 (br. s., 2H), 4.99 (s, 2H), 1.25 (br. s., 3H). 10

355.18 356 1.86, V3018V3001 4 >260 ¹H NMR (500 MHz, MeOD) δ ppm 6.83 (s,1H), 3.95 (dd, J = 2.84, 11.35 Hz, 2H), 3.87 (d, J = 7.57 Hz, 2H),3.36-3.44 (m, 2H), 2.25-2.37 (m, 1H), 1.89-1.98 (m, 1H), 1.60 (dd, J =1.89, 12.93 Hz, 2H), 1.41-1.52 (m, 2H), 0.88-0.96 (m, 2H), 0.71-0.77 (m,2H). 11

365.16 366 2.11, V3018V3001 2 >260 ¹H NMR (DMSO-d₆, 500 MHz): δ ppm10.47 (br. s., 1H), 7.22-7.38 (m, 5H), 7.20 (s, 1H), 6.91 (s, 1H), 6.62(br. s., 2H), 4.97 (s, 2H), 4.52 (t, J = 5.4 Hz, 2H), 3.48 (t, J = 5.4Hz, 2H), 3.10 (s, 3H) 12

321.13 322 2.06, V3018V3001 2 >260 ¹H NMR (DMSO-d₆, 500 MHz): δ ppm7.16-7.33 (m, 5H), 7.10 (s, 1H), 6.84 (s, 1H), 6.24 (br. s., 2H), 4.91(s, 2H), 3.85 (s, 3H) 15

319.12 320 2.3,  Villa 6 ¹H NMR (DMSO-d₆, 300 MHz): δ ppm 10.25 (br. s,1H), 9.47 (s, 2H), 9.23 (s, 1H), 7.40 (t, J = 7.2 Hz, 2H), 7.34 (t, J =7.2 Hz, 2H), 7.27 (d, J = 7.2 Hz, 1H) 6.70 (s, 2H), 5.75 (s, 1H), 5.02(s, 2H) 18

306.12 307 2.45, Villa 6 ¹H NMR (DMSO-d₆, 300 MHz): δ ppm 11.10 (br. s.,1H), 10.20 (br. s., 1H), 7.43 (d, J = 7.1 Hz, 2H), 7.33 (t, J = 7.1 Hz,2H), 7.26 (t, J = 7.1 Hz, 1H), 6.83 (d, J = 1.5 Hz, 1H), 6.68 (br. s.,1H), 6.35 (s, 2H), 6.10 (d, J = 1.5 Hz, 1H), 4.98 (s, 2H) 19

307.12 308 1.82, Villa 6 ¹H NMR (DMSO-d₆, 300 MHz): δ ppm 12.97 (br. s.,1H), 10.25 (br. s., 1H), 8.02 (br. s., 2H), 7.18- 7.44 (m, 5H), 6.42 (s,2H), 4.95 (s, 2H) 20

307.11 308 2.57, Villa 6 ¹H NMR (DMSO-d₆, 300 MHz): δ ppm 10.60 (br. s.,1H), 7.76 (br. s, 1H), 7.19- 7.40 (m, 5H), 7.00 (d, J = 3.3 Hz, 1H),6.66 (s, 2H), 6.59 (dd, J = 3.3, 1.8 Hz, 1H), 5.0 (s, 2H) 23

307.12 308 2.03, V3018V3001 5 >260 ¹H NMR (500 MHz, DMSO-d₆) δ ppm12.84-13.37 (m, 1H), 10.30 (br. s., 1H), 7.23-7.76 (m, 6H), 6.70 (br.s., 1H), 6.49 (br. s., 2H), 4.98 (s, 2H). 24

362.16 363 2.20  V3018V3001 4 240 ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 12.25(br. s., 1H), 7.18 (d, J = 8.1 Hz, 1H), 6.99-7.14 (m, 4H), 6.50 (s, 2H),4.94 (s, 2H), 3.93 (s, 2H), 3.01-3.07 (m, 2H), 2.72 (t, J = 5.6 Hz, 2H)25

390.19 391 2.47  V3018V3001 4 196 ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 12.13(br. s, 1H), 10.38 (br. s, 1H), 8.15 (br. s., 0.49 H, formate salt pic),7.39 (br. s., 1H), 7.18- 7.34 (m, 3H), 7.09 (br. s., 2H), 6.50 (br. s.,2H), 5.01 (br. s., 2H), 3.71 (br. s, 2H), 2.50-2.61 (m, 4H), 1.67 (br.s., 4H) 26

362.16 363 1.90  V3018V3001 4 >260 ¹H NMR (DMSO-d₆, 400 MHz) : δ ppm12.05 (s br, 1H), 10.27 (s, 1H), 8.56 (d, J = 1.8 Hz, 1H), 8.15 (s,0.59H, formate salt pic), 7.70 (dd, J = 8.2, 1.8 Hz, 1H), 7.20 (d, J =8.2 Hz, 1H), 6.93 (s br, 1H), 6.49 (s br, 2H), 4.97 (s, 2H), 2.41 (s,3H), 1.78- 1.90 (m, 1H), 0.70- 0.87 (m, 2H), 0.64- 0.70 (m, 2H) 27

351.14 352 1.78  V3018V3001 2 260 ¹H NMR (DMSO-d₆, 500 MHz): δ ppm 10.37(s, 1H), 7.23- 7.38 (m, 5H), 7.21 (d, J = 0.9 Hz, 1H), 6.91 (d, J = 0.9Hz, 1H), 6.58 (br. s., 2H), 4.96 (s, 2H), 4.81 (t, J = 5.7 Hz, 1H), 4.41(t, J = 5.7 Hz, 2H), 3.59 (q, J = 5.7 Hz, 2H) 28

363.18 364 2.51  V3018V3001 2 >260 ¹H NMR (DMSO-d₆, 500 MHz): δ ppm11.78-12.24 (m, 1H), 10.28 (s, 1H), 7.07-7.47 (m, 5H), 6.21-6.93 (m,3H), 5.01 (s,H), 1.13- 1.45 (m, 9H) 29

349.17 350 2.35  V3018V3001 2 >260 ¹H NMR (DMSO-d₆, 500 MHz): δ ppm11.80-12.14 (m, 1H), 10.41 (br. s., 1H), 7.06-7.70 (m, 5H), 6.65-6.89(m, 1H), 6.37-6.62 (m, 2H), 4.89-5.21 (m, 2H), 2.73-3.16 (m, 1H),1.04-1.31 (m, 6H) 30

335.15 336 2.18  V3018V3001 2 >260 ¹H NMR (DMSO-d₆, 500 MHz): δ ppm11.82-12.28 (m, 1H), 10.47 (br. s., 1H), 7.08-7.56 (m, 5H), 6.63-7.01(m, 1H), 6.38-6.59 (m, 2H), 4.78-5.07 (m, 2H), 2.53-2.69 (m, 2H),0.95-1.35 (m, 3H) 31

375.11 376 2.38  V3018V3001 2 >260 ¹H NMR (DMSO-d₆, 500 MHz): δ ppm13.07 (br. s., 1H), 10.46 (br. s., 1H), 7.83 (s, 1H), 7.39 (d, J = 8.2Hz, 2H), 7.32 (t, J = 8.2 Hz, 2H), 7.26 (t, J = 8.2 Hz, 1H), 6.65 (br.s., 2H), 4.98 (s, 2H) 32

308.10 309 2.06  V3018V3001 5 ¹H NMR (DMSO-d₆, 500 MHz): δ ppm 10.44(br. s., 1H), 8.45 (s, 1H), 7.63 (s, 1H), 7.16-7.37 (m, 5H), 6.70 (br.s., 2H), 4.96 (s, 2H) 33

323.11 324 2.23  V3018V3001 5 >250 ¹H NMR (DMSO-d₆, 500 MHz): δ ppm10.72 (br. s., 1H), 7.11-7.56 (m, 5H), 6.94 (br. s., 2H), 5.00 (br. s.,2H), 2.41 (s, 3H) 34

367.14 368 2.27  V3018V3001 5 >250 ¹H NMR (DMSO-d₆, 500 MHz): δ ppm10.71 (br. s., 1H), 7.16-7.49 (m, 5H), 6.96 (br. s., 2H), 5.01 (s, 2H),3.72 (t, J = 6.3 Hz, 2H), 3.24 (s, 3H), 3.01 (t, J = 6.3 Hz, 2H) 35

321.13 322 2.42  V3018V3001 7 >260 ¹H NMR (DMSO-d₆, 500 MHz): δ ppm10.31 (br. s., 1H), 8.24 (s, 1H), 7.51 (s, 1H), 7.18-7.40 (m, 5H), 6.78(br. s., 2H), 4.96 (s, 2H), 2.08 (s, 3H) 36

307.12 308 2.25  V3018V3001 7 >260 ¹H NMR (DMSO-d₆, 500 MHz): δ ppm10.33 (br. s., 1H), 8.46 (d, J = 2.5 Hz, 1H), 7.70 (s, 1H), 7.20-7.40(m, 5H), 6.82 (br. s., 2H), 6.48 (d, J = 3.8 Hz, 1H), 4.97 (s, 2H) 37

365.12 366 2.24  V3018V3001 8 ¹H NMR (DMSO-d₆, 400 MHz): δ (ppm) 9.80(br. s., 1H), 8.47 (d, J = 2.5 Hz, 1H), 7.99 (s, 1H), 7.87 (d, J = 7.6Hz, 1H), 7.70 (s, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.50 (t, J = 7.6 Hz,1H), 6.84 (br. s, 2H), 6.43- 6.63 (m, 1H), 5.04 (s, 2H), 3.83 (s, 3H) 38

351.11 352 2.27  V3014V3001 8 332 ¹H NMR (DMSO-d₆, 400 MHz): δ (ppm)13.01 (br. s., 1H), 10.46 (br. s., 1H), 8.47 (s, 1H), 7.95 (s, 1H), 7.84(d, J = 7.6 Hz, 1H), 7.69 (s, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.46 (t, J= 7.6 Hz, 1H), 6.87 (br. s., 2H), 6.48 (s, 1H), 5.03 (s, 2H) 39

337.13 338 1.87  V3018V3001 8 ¹H NMR (DMSO-d₆, 500 MHz): δ (ppm) 10.28(br. s., 1H), 8.46 (s, 1H), 7.70 (s, 1H), 7.10-7.37 (m, 4H), 6.82 (br.s., 2H), 6.35-6.57 (m, 1H), 5.17 (t, J = 5.7 Hz, 1H), 4.96 (s, 2H), 4.45(d, J = 5.7 Hz, 2H) 40

457.16 458 2.13  V3018V3001 8 218 ¹H NMR (DMSO-d₆, 500 MHz): δ (ppm)10.41 (br. s., 1H), 8.46 (br. s., 1H), 7.69 (s, 1H), 7.04-7.38 (m, 4H),6.85 (br. s., 2H), 6.47 (br. s., 1H), 4.95 (br. s., 2H), 3.85 (quin, J =7.0 Hz, 4H), 3.18 (d, J = 21.4 Hz 2H), 1.06 (t, J = 7.0 Hz, 6H) 41

401.10 402 5.40  V2012V2002 8 101 ¹H NMR (DMSO-d₆, 400 MHz): δ (ppm)10.43 (s, 1H), 8.46 (d, J = 2.5 Hz, 1H), 7.69 (s, 1H), 7.10- 7.31 (m,4H), 6.84 (br. s., 2H), 6.47 (dd, J = 2.5, 1.5 Hz, 1H), 6.29 (br. s,2H), 4.90 (s, 2H), 2.92 (d, J = 21.2 Hz, 2H) 42

338.12 339 2.45  V3014V3001 7 ¹H NMR (DMSO-d₆, 500 MHz): δ (ppm) 10.20(br. s., 1H), 8.37 (d, J = 2.2 Hz, 1H), 7.65 (s, 1H), 7.48 (d, J = 6.9Hz, 1H), 7.19 (t, J = 6.9 Hz, 1H), 6.82-7.00 (m, 3H), 6.44 (dd, J = 2.4,1.7 Hz, 1H), 4.95-5.14 (m, 2H), 2.43 (s, 3H) 43

347.12 348 2.54  V3014V3001 7 ¹H NMR (DMSO-d₆, 400 MHz): δ (ppm)12.48-13.42 (m, 1H), 9.90-10.57 (m, 1H), 8.44 (d, J = 9.1 Hz, 1H),7.37-7.99 (m, 3H), 7.19 (t, J = 9.1 Hz, 1H), 6.83 (t, J = 9.1 Hz, 1H),6.69 (br. s., 1H), 6.47 (br. s., 2H), 5.12 (br. s., 2H) 44

365.12 366 3.05  V3018V3001 7 ¹H NMR (DMSO-d₆, 400 MHz): δ (ppm)12.32-13.87 (m, 1H), 9.94-10.53 (m, 1H), 7.4-8.26 (m, 5H), 6.61-6.89 (m,1H), 6.28-6.59 (m, 2H), 5.05 (s, 2H), 3.83 (s, 3H) 45

351.11 352 2.13  V3014V3001 7 ¹H NMR (DMSO-d₆, 400 MHz): δ (ppm) 13.06(br. s., 2H), 10.32 (br. s., 1H), 7.97 (s, 1H), 7.83 (d, J = 7.6 Hz,1H), 7.69 (d, J = 7.6 Hz, 1H), 7.57 (br. s., 1H), 7.46 (t, J = 7.6 Hz,1H), 6.72 (d, J = 1.5 Hz, 1H), 6.48 (s, 2H), 5.04 (s, 2H) 46

337.13 338 1.63  V3018V3001 7 >260 ¹H NMR (DMSO-d₆, 500 MHz): δ (ppm)12.48-13.52 (m, 1H), 9.83-10.74 (m, 1H), 7.01-7.98 (m, 5H), 6.22-6.84(m, 3H), 5.17 (t, J = 5.7 Hz, 1H), 4.97 (s, 2H), 4.44 (d, J = 5.7 Hz,2H) 47

485.19 486 2.11  V3018V3001 2 ¹H NMR (DMSO-d₆, 400 MHz): δ (ppm) 10.45(s, 1H), 7.13- 7.54 (m, 6H), 6.94 (s, 1H), 6.62 (br. s., 2H), 4.98 (s,2H), 4.33- 4.48 (m, 2H), 3.82- 4.02 (m, 4H), 1.76- 1.92 (m, 2H), 1.47-1.66 (m, 2H), 1.15 (t, J = 6.8 Hz, 6H) 48

347.12 348 1.81  V3018V3001 8 ¹H NMR (DMSO-d₆, 400 MHz): δ (ppm) 10.35(br. s., 1H), 8.27-8.53 (m, 2H), 7.77 (s, 1H), 7.67 (s, 1H), 7.47 (d, J= 9.1 Hz, 1H), 7.15-7.27 (m, 1H), 6.76-6.88 (m, 3H), 6.36-6.53 (m, 1H),5.09 (s, 2H) 49

368.13 369 1.94  V3018V3001 8 >260 ¹H NMR (DMSO-d₆, 500 MHz): δ (ppm)9.42-10.55 (m, 1H), 8.35 (d, J = 2.5 Hz, 1H), 8.01 (d, J = 5.4 Hz, 1H),7.65 (s, 1H), 7.02 (d, J = 5.4 Hz, 1H), 6.80 (br. s., 2H), 6.36-6.55 (m,1H), 5.07 (s, 2H), 3.81- 3.96 (m, 6H) 50

322.13 323 2.78  V3014V3001 8 >260 ¹H NMR (DMSO-d₆, 500 MHz): δ (ppm)10.31 (br. s., 1H), 8.49 (d, J = 8.5 Hz, 2H), 7.71 (s, 1H), 7.65 (d, J =7.6 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 6.82 (br. s., 2H), 6.50 (br. s.,1H), 4.95 (s, 2H), 2.39 (s, 3H) 51

347.15 348 2.35  V3018V3001 7 >260 ¹H NMR (DMSO-d₆, 500 MHz): δ (ppm)12.36-12.99 (m, 1H), 10.33 (br. s., 1H), 6.94-7.75 (m, 5H), 5.99-6.73(m, 3H), 4.97 (s, 2H), 1.81-1.97 (m, 1H), 0.54-1.02 (m, 4H) 52

351.14 352 1.93  V3018V3001 7 ¹H NMR (DMSO-d6, 400 MHz): δ (ppm) 10.23(br. s., 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.15-7.40 (m, 5H), 6.72 (d, J =2.0 Hz, 1H), 6.46 (s, 2H), 4.97 (s, 2H), 4.87 (t, J = 5.1 Hz, 1H), 4.17(t, J = 5.1 Hz, 2H), 3.75 (q, J = 5.1 Hz, 2H) 53

321.13 322 2.26  V3018V3001 7 192 ¹H NMR (DMSO-d₆, 500 MHz): δ (ppm)12.94 (br. s., 1H), 10.28 (s, 1H), 7.17- 7.49 (m, 6H), 6.41 (br. s.,2H), 4.97 (s, 2H), 2.28-2.39 (m, 3H) 54

435.21 436 1.32  V3018V3001 2 211 ¹H NMR (DMSO-d₆, 500 MHz): δ (ppm)11.90-12.42 (m, 1H), 10.14 (br. s., 1H), 7.85-8.01 (m, 1H), 7.35-7.56(m, 1H), 6.21-7.07 (m, 4H), 4.65-4.77 (m, 2H), 3.86-3.94 (m, 2H),2.38-2.44 (m, 2H), 2.04 (s, 6H), 1.77-1.89 (m, 1H), 0.60-0.92 (m, 4H) 55

404.17 405 2.80  V3014V3001 2 218 ¹H NMR (DMSO-d₆, 400 MHz): δ (ppm)12.52 (br. s., 1H), 10.32 (s, 1H), 7.59 (s, 1H), 7.46-7.51 (m, 1H),7.34-7.45 (m, 2H), 7.12 (br. s., 2H), 6.49 (s, 2H), 4.94-5.25 (m, 2H),3.41 (t, J = 7.1 Hz, 2H), 3.20-3.29 (m, 2H), 1.79 (quin, J = 7.1 Hz,2H), 1.64 (quin, J = 7.1 Hz, 2H) 57

396.13 397 1.79  V3018V3001 2 >260 ¹H NMR (DMSO-d₆, 500 MHz): δ (ppm)12.47 (br. s., 1H), 10.30 (br. s., 1H), 8.25 (br. s., 1H), 7.84 (d, J =8.2 Hz, 1H), 7.13 (br. s., 2H), 6.90 (d, J = 8.2 Hz, 1H), 6.50 (br. s.,2H), 4.94 (br. s., 2H), 4.87 (br. s., 2H), 3.63 (s, 3H) 58

382.11 383 2.00  V3014V3001 2 >260 ¹H NMR (DMSO-d₆, 500 MHz): δ (ppm)11.87-13.45 (m, 2H), 10.50 (br. s., 1H), 8.27 (br. s., 1H), 7.83 (d, J =7.6 Hz, 1H), 7.22 (br. s., 2H), 6.86 (d, J = 7.6 Hz, 1H), 6.61 (br. s.,2H), 4.94 (br. s., 2H), 4.77 (br. s., 2H) 60

402.19 403 2.61  V3014V3001 2 242 ¹H NMR (DMSO-d₆, 400 MHz): δ (ppm)8.98-12.14 (m, 1H), 8.21 (s, 1H), 6.04- 7.47 (m, 6H), 4.95 (br. s., 2H),4.02 (br. s., 2H), 3.13 (br. s., 2H), 2.79 (br. s., 2H), 1.67-1.97 (m,1H), 0.42-0.94 (m, 4H) 61

385.23 386 2.14  V3014V3001 2 ¹H NMR (DMSO-d₆, 400 MHz): δ (ppm) 11.85(br. s., 1H), 10.32 (s, 1H), 7.09 (s, 2H), 6.46 (s, 2H), 3.81 (t, J =7.2 Hz, 2H), 2.30-2.48 (m, 10H), 2.27 (s, 3H), 1.74 (quin, J = 7.2 Hz,2H), 1.49 (quin, J = 7.2 Hz, 2H), 1.20- 1.36 (m, 2H) 62

410.25 411 1.67  V3018V3001 2 174 ¹H NMR (DMSO-d₆, 500 MHz): δ (ppm)11.91 (br. s., 1H), 10.29 (br. s., 1H), 6.84 (br. s., 1H), 6.49 (br. s.,2H), 3.79 (t, J = 6.9 Hz, 2H), 2.52- 2.70 (m, 6H), 1.80- 1.90 (m, 1H),1.71 (br. s., 5H), 1.39- 1.52 (m, 2H), 1.17- 1.38 (m, 5H), 0.51- 0.91(m, 4H) 63

315.14 3.16 2.37  V3014V3001 2 >260 ¹H NMR (DMSO-d₆, 400 MHz): δ (ppm)12.35 (br. s., 1H), 10.24 (br. s., 1H), 7.11 (br. s., 2H), 6.44 (s, 2H),3.78-3.87 (m, 2H), 3.70 (d, J = 7.1 Hz, 2H), 3.24 (t, J = 10.9 Hz, 2H),1.99-2.18 (m, 1H), 1.08-1.76 (m, 4H)

Analytical Methods.

All compounds were characterized by LC-MS. The following LC-MS methodswere used:

Method VILLA:

All analyses were performed using an Agilent 1100 series LC/MSDquadrupole coupled to an Agilent 1100 series liquid chromatography (LC)system consisting of a binary pump with degasser, autosampler,thermostated column compartment and diode array detector. The massspectrometer (MS) was operated with an atmospheric pressureelectro-spray ionisation (API-ES) source in positive ion mode. Thecapillary voltage was set to 3000 V, the fragmentor voltage to 70 V andthe quadrupole temperature was maintained at 100° C. The drying gas flowand temperature values were 12.0 L/min and 350° C. respectively.Nitrogen was used as the nebulizer gas, at a pressure of 35 psig. Dataacquisition was performed with Agilent Chemstation software.

In addition to the general procedure, analyses were carried out on a YMCpack ODS-AQ C18 column (50 mm long×4.6 mm i.d.; 3 μm particles) at 35°C., with a flow rate of 2.6 mL/min. A gradient elution was performedfrom 95% (water+0.1% formic acid)/5% Acetonitrile to 5% (water+0.1%formic acid)/95% Acetonitrile in 4.80 minutes, then the final mobilephase composition was held for an additional 1.00 min. The standardinjection volume was 2 μL. Acquisition ranges were set to 190-400 nm forthe UV-PDA detector and 100-1400 m/z for the MS detector.

Method B ACQUITY UPLC System with SQD-Detector

Mobile Phase: A: Methanol, B: 10 mM Ammonium Acetate in 90% Water and10% Acetonitrile

Column: Type column: Aquity UPLC BEH C18 1.7 μm 2.1×50 mm Column (WatersNo 186002350), Temperature: 70° C. Gradient timetable. Flow: 0.7 ml/min,Acquisition stop: 1.8 min. Stop time: 2 min.

Time Flow (min.) % A % B (ml/min.) 0.00 5 95 0.7 1.30 95 5 0.7 1.50 95 50.7 1.70 5 95 0.7 2.00 5 95 0.7Injection Vol.: 0.75 μl. Inject Type: Partial Loop With Needle OverfillStart wavelength: 210 nm. End wavelength: 400 nm. Resolution: 1.2 nm.Sampling Rate: 20 points/sec

MS-method: Function 1: Ion Mode: ES+, Data Format: Centroid Start Mass:160. End Mass: 1000

Scan time (sec): 0.1, Start Time (min): 0.0, End Time (min): 2.0, ConeVoltage (V): 30

Function 2: Ion Mode: ES−, Data Format: Centroid, Start Mass: 160, EndMass: 1000

Scan time (sec): 0.1, Start Time (min): 0.0, End Time (min): 2.0, ConeVoltage (V): 30,Flow in MS: 700 μl/minGeneral Procedure VDR1 (for Methods V100xV10xx.olp and V200xV20xx.olp)

The HPLC measurement was performed using an Alliance HT 2795 (Waters)system comprising a quaternary pump with degasser, an autosampler, adiode-array detector (DAD) and a column as specified in the respectivemethods below, the column is hold at a temperature of 30° C. Flow fromthe column was split to a MS spectrometer. The MS detector wasconfigured with an electrospray ionization source. The capillary needlevoltage was 3 kV and the source temperature was maintained at 100° C. onthe LCT (Time of Flight Zspray™ mass spectrometer from Waters—formethods V100xV10xx.olp), and 3.15 kV at 110° C. on the ZQ™ (simplequadrupole Zspray™ mass spectrometer from Waters—for methodsV200xV20xx.olp). Nitrogen was used as the nebulizer gas. Dataacquisition was performed with a Waters-Micromass MassLynx-Openlynx datasystem.

General Procedure VDR2 (for Methods V300xV30xx.olp)

The LC measurement was performed using a UPLC (Ultra Performance LiquidChromatography) Acquity (Waters) system comprising a binary pump withdegasser, an autosampler, a diode-array detector (DAD) and a column asspecified in the respective methods below, the column is hold at atemperature of 40° C. Flow from the column was brought to a MS detector.The MS detector was configured with an electrospray ionization source.The capillary needle voltage was 3 kV and the source temperature wasmaintained at 130° C. on the Quattro (triple quadrupole massspectrometer from Waters). Nitrogen was used as the nebulizer gas. Dataacquisition was performed with a Waters-Micromass MassLynx-Openlynx datasystem.

Method V1005V1012

In addition to the general procedure VDR1: Reversed phase HPLC wascarried out on a Waters X-bridge C18 column (3.5 μm, 4.6×100 mm) with aflow rate of 0.8 ml/min. Two mobile phases (mobile phase A: 100% 7 mMammonium acetate; mobile phase B: 100% acetonitrile) were employed torun a gradient condition from 80% A and 20% B (hold for 0.5 minute) to90% B in 4.5 minutes, 90% B for 4 minutes and reequilibrated withinitial conditions for 3 minutes. An injection volume of 5 μl was used.Cone voltage was 20 V for positive and negative ionization mode. Massspectra were acquired by scanning from 100 to 1000 in 0.4 seconds usingan interscan delay of 0.3 seconds.

Method V1004V1012

In addition to the general procedure VDR1: Reversed phase HPLC wascarried out on a Kromasil C18 column (3.5 μm, 4.6×100 mm) with a flowrate of 0.85 ml/min. Three mobile phases (mobile phase A: 100% 7 mMammonium acetate; mobile phase B: 100% acetonitrile; mobile phase C:0.2% formic acid+99.8% ultra-pure Water) were employed to run a gradientcondition from 35% A, 30% B and 35% C (hold for 1 minute) to 100% B in 3minutes, 100% B for 4.5 minutes and reequilibrated with initialconditions for 3 minutes. An injection volume of 5 μl was used. Conevoltage was 20 V for positive and negative ionization mode. Mass spectrawere acquired by scanning from 100 to 1000 in 0.4 seconds using aninterscan delay of 0.3 seconds.

Method V1010V1012

In addition to the general procedure VDR1: Reversed phase HPLC wascarried out on a Waters Atlantis C18 column (5 μm, 3.9×100 mm) with aflow rate of 0.8 ml/min. Three mobile phases (mobile phase A: 100% 7 mMammonium acetate; mobile phase B: 100% acetonitrile; mobile phase C:0.2% formic acid+99.8% ultra-pure water) were employed to run a gradientcondition from 50% A and 50% C (hold for 1.5 minute) to 10% A, 80% B and10% C in 4.5 minutes, hold for 4 minutes and reequilibrated with initialconditions for 3 minutes. An injection volume of 5 μl was used. Conevoltage was 20 V for positive and negative ionization mode. Mass spectrawere acquired by scanning from 100 to 1000 in 0.4 seconds using aninterscan delay of 0.3 seconds.

Method V2002V2002+LCpos_court.olp

In addition to the general procedure VDR1: Reversed phase HPLC wascarried out on a Kromasil C18 column (3.5 μm, 4.6×100 mm) with a flowrate of 0.8 ml/min. Three mobile phases (mobile phase A: 100% 7 mMammonium acetate; mobile phase B: 100% acetonitrile; mobile phase C:0.2% formic acid+99.8% ultra-pure water) were employed to run a gradientcondition from 35% A, 30% B and 35% C (hold for 1 minute) to 100% B in 4minutes, 100% B for 4 minutes and reequilibrated with initial conditionsfor 2 minutes. An injection volume of 10 μl was used. Cone voltage was20 V for positive and negative ionization mode. Mass spectra wereacquired by scanning from 100 to 1000 in 0.4 seconds using an interscandelay of 0.3 seconds.

Method V2003V2002

In addition to the general procedure VDR1: Reversed phase HPLC wascarried out on a X-Bridge C18 column (3.5 μm, 4.6×100 mm) with a flowrate of 0.8 ml/min. Two mobile phases (mobile phase A: 100% 7 mMammonium acetate; mobile phase B: 100% acetonitrile; were employed torun a gradient condition from 80% A, 20% B (hold for 0.5 minute) to 10%A, 90% B in 4.5 minutes, hold at 10% A and 90% B for 4 minutes andreequilibrated with initial conditions for 3 minutes. An injectionvolume of 10 μl was used. Cone voltage was 20 V for positive andnegative ionization mode. Mass spectra were acquired by scanning from100 to 1000 in 0.4 seconds using an interscan delay of 0.3 seconds.

Method V2012V2002

In addition to the general procedure VDR1: Reversed phase HPLC wascarried out on a Waters Atlantis C18 column (5 μm, 3.9×100 mm) with aflow rate of 0.8 ml/min. Three mobile phases (mobile phase A: 100% 7 mMammonium acetate; mobile phase B: 100% acetonitrile; mobile phase C:0.2% formic acid+99.8% ultra-pure Water) were employed to run a gradientcondition from 50% A, 0% B and 50% C (hold for 1.5 minutes) to 10% A,80% B and 10% in 3.5 minutes, hold in these conditions for 4 minutes andreequilibrated with initial conditions for 3 minutes. An injectionvolume of 10 μl was used. Cone voltage was 20 V for positive andnegative ionization mode. Mass spectra were acquired by scanning from100 to 1000 in 0.4 seconds using an interscan delay of 0.3 seconds.

Method V2015V2007

In addition to the general procedure VDR1: Reversed phase HPLC wascarried out on a Supelco Ascentis Express C18 column (2.7 μm, 3.0×50 mm)with a flow rate of 0.7 ml/min. Two mobile phases (mobile phase A: 100%7 mM ammonium acetate; mobile phase B: 100% acetonitrile) were employedto run a gradient condition from 80% A and 20% B (hold for 0.5 minute)to 5% A and 95% B in 2.5 minutes, hold for 4.5 minutes and back toinitial conditions in 1.5 minutes and hold for 1 min. An injectionvolume of 5 ml was used. Cone voltage was 20 V for positive and negativeionization mode. Mass spectra were acquired by scanning from 100 to 1000in 0.4 seconds using an interscan delay of 0.3 seconds.

Method V3018V3001

In addition to the general procedure VDR2: Reversed phase UPLC wascarried out on a Waters Acquity BEH (bridged ethylsiloxane/silicahybrid) C18 column (1.7 μm, 2.1×100 mm) with a flow rate of 0.343ml/min. Two mobile phases (mobile phase A: 95% 7 mM ammonium acetate/5%acetonitrile; mobile phase B: 100% acetonitrile) were employed to run agradient condition from 84.2% A and 15.8% B (hold for 0.49 minutes) to10.5% A and 89.5% B in 2.18 minutes, hold for 1.94 min and back to theinitial conditions in 0.73 min, hold for 0.73 minutes. An injectionvolume of 2 μl was used. Cone voltage was 20V for positive and negativeionization mode. Mass spectra were acquired by scanning from 100 to 1000in 0.2 seconds using an interscan delay of 0.1 seconds.

Method V3014V3001

In addition to the general procedure VDR2: Reversed phase UPLC wascarried out on a Waters HSS (High Strength Silica) T3 column (1.8 μm,2.1×100 mm) with a flow rate of 0.35 ml/min. Two mobile phases (mobilephase A: 95% 7 mM ammonium acetate/5% acetonitrile; mobile phase B: 100%acetonitrile) were employed to run a gradient condition from 99% A (holdfor 0.5 minutes) to 15% A and 85% B in 4.5 minutes, hold for 2 min andback to the initial conditions in 0.5 min, hold for 1.5 minutes. Aninjection volume of 2 □l was used. Cone voltage was 20 V for positiveand negative ionization mode. Mass spectra were acquired by scanningfrom 100 to 1000 in 0.2 seconds using an interscan delay of 0.1 seconds.

Biological Activity of Compounds of Formula (I) Description ofBiological Assays Reporter Assays for Assessment of TLR7 Activity (24 h)

The ability of compounds to activate human TLR7 was assessed in acellular reporter assay using HEK293 cells transiently transfected witha TLR7 or TLR8 expression vector and NFκB-luc reporter construct. In oneinstance the TLR expression construct expresses the respective wild typesequence or a mutant sequence comprising a deletion in the secondleucine-rich repeat (dIRR2) of the TLR. Such mutant TLR proteins havepreviously been shown to be more susceptible to agonist activation (U.S.Pat. No. 7,498,409).

Briefly, HEK293 cells were grown in culture medium (DMEM supplementedwith 10% FCS and 2 mM Glutamine). For transfection of cells in 10 cmdishes, cells were detached with Trypsin-EDTA, transfected with a mix ofCMV-TLR7 or TLR8 plasmid (750 ng), NFκB-luc plasmid (375 ng) and atransfection reagent and incubated 24 hours or 48 hours respectively at37° C. in a humidified 5% CO2 atmosphere. Transfected cells were thendetached with Trypsin-EDTA, washed in PBS and resuspended in medium to adensity of 1.67×105 cells/mL. Thirty microliters of cells were thendispensed into each well in 384-well plates, where 10 μL of compound in4% DMSO was already present. Following 6 hours incubation at 37° C., 5%CO2, the luciferase activity was determined by adding 15 μl of SteadyLite Plus substrate (Perkin Elmer) to each well and readout performed ona ViewLux ultraHTS microplate imager (Perkin Elmer). Dose responsecurves were generated from measurements performed in quadruplicates.Lowest effective concentrations (LEC) values, defined as theconcentration that induces an effect which is at least two fold abovethe standard deviation of the assay, were determined for each compound.Compound toxicity was determined in parallel using a similar dilutionseries of compound with 30 μL per well of cells transfected with theCMV-TLR7 construct alone (1.67×105 cells/mL), in 384-well plates. Cellviability was measured after 6 hours incubation at 37° C., 5% CO2 byadding 15 μL of ATP lite (Perkin Elmer) per well and reading on aViewLux ultraHTS microplate imager (Perkin Elmer). Data was reported asCC50.

Measurement of Interferon Production in Human PBMC (PBMC-HUH7_EC50)

Activation of human TLR7 results in robust production of interferon byplasmacytoid dendritic cells present in human blood. The potential ofcompounds to induce interferon was evaluated by looking at the antiviralactivity in the HCV replicon system upon incubation with conditionedmedia from peripheral blood mononuclear cells (PBMC). The HCV repliconassay is based on a bicistronic expression construct, as described byLohmann et al. (Science (1999) 285: 110-113; Journal of Virology (2003)77: 3007-15 3019) with modifications described by Krieger et al.(Journal of Virology (2001) 75: 4614-4624). The assay utilized thestably transfected cell line Huh-7 luc/neo harboring an RNA encoding abicistronic expression construct comprising the wild type NS3-NS5Bregions of HCV type 1b translated from an Internal Ribosome Entry Site(IRES) from encephalomyocarditis virus (EMCV), preceded by a reportergene (Firefly-luciferase) and a selectable marker gene (neoR, neomycinephosphotransferase). The construct is flanked by 5′ and 3′ NTRs(non-translated regions) from HCV type 1b. Continued culture of thereplicon cells in the presence of G418 (neoR) is dependent on thereplication of the HCV RNA. The stably transfected replicon cells thatreplicate HCV RNA autonomously and to high levels, encoding inter alialuciferase, were used for profiling of the conditioned cell culturemedia. Briefly, PBMCs were prepared from buffy coats of at least twodonors using a standard Ficoll centrifugation protocol. Isolated PBMCswere resuspended in RPMI medium supplemented with 10% human AB serum and2×105 cells/well were dispensed into 384-well plates containingcompounds (70 μL total volume). After overnight incubation, μL ofsupernatant was transferred to 384-well plates containing 2.2×103replicon cells/well in 30 μL (plated the day before). Following 24 hoursof incubation, replication was measured by assaying luciferase activityusing 40 μL/well Steady Lite Plus substrate (Perkin Elmer) and measuredwith ViewLux ultraHTS microplate imager (Perkin Elmer). The inhibitoryactivity of each compound on the Huh7-luc/neo cells were reported asEC50 values, defined as the compound concentration applied to the PBMCsresulting in a 50% reduction of luciferase activity which in turnindicates the degree of replication of the replicon RNA on transfer of adefined amount of PBMC culture medium. Recombinant interferon α-2a(Roferon-A) was used as a standard control compound. All compoundsshowed CC50 of >24 μM in the HEK 293 TOX assay described above.

Measurement of Interferon Production in Human PBMC (PBMC HEK-ISRE-LucLEC)

Activation of human TLR7 results in robust production of interferon byplasmacytoid dendritic cells present in human blood. The potential ofcompounds to induce interferon was evaluated by determination ofinterferon in the conditioned media from peripheral blood mononuclearcells (PBMC). The presence of interferon in the samples was determined,using an interferon reporter cell line stably expressing aninterferon-stimulated responsive elements (ISRE)-luc reporter construct.The ISRE element with sequence GAAACTGAAACT (SEQ ID NO: 1) is highlyresponsive to the STAT1-STAT2-IRF9 transcription factor, which becomesactivated upon binding of IFN-I to the IFN receptor. Briefly, PBMCs wereprepared from buffy coats of at least two donors using a standard Ficollcentrifugation protocol. Isolated PBMCs were resuspended in RPMI mediumsupplemented with 10% human AB serum and 2×105 cells/well were dispensedinto 384-well plates containing compounds (70 μL total volume). Afterovernight incubation of the PBMCs with the compounds, 10 μL ofsupernatant was transferred to 384-well plates containing 5×103HEK-ISRE-luc cells/well in 30 μL (plated the day before). Following 24hours of incubation, activation of the ISRE elements was measured byassaying luciferase activity using 40 μL/well Steady Lite Plus substrate(Perkin Elmer) and measured with ViewLux ultraHTS microplate imager(Perkin Elmer). The stimulating activity of each compound on theHEK-ISRE-luc cells was reported as LEC. The LEC in turn indicates thedegree of ISRE activation on transfer of a defined amount of PBMCculture medium. Recombinant interferon alfa-2a (Roferon-A) was used as astandard control compound.

The LEC values for the compounds in table 2 on HEK293 TLR8-NF□B-luc andHEK293 NF□B-luc where greater than the highest tested concentration (>10μM for compound 6 and >25 μM for all other compounds).

TABLE 2 Biological activity of compounds of formula (I) PBMC HEK- ISRE-TLR7- TLR7- TLR7- TLR7- PBMC- luc wt_LEC dIRR2_LEC wt_LEC dIRR2_LECHUH7_EC50 (LEC; # STRUCTURE 24 h (μM) 24 h (μM) 48 h (μM) 48 h (μM) (μM)μM) 1

0.33 8.25 0.18 0.081 0.064 2

4.72 1.2 0.531 3

>24.59 7.67 13.97 4

0.077 1.23 0.04 0.16 0.12 5

2.2 21.47 1.13 0.2 0.13 6

0.66 6.32 0.34 0.053 0.04 7

>25 1.46 0.64 0.88 8

5.91 0.17 0.17 0.25 9

0.88 0.07 0.05 0.03 10

18.93 >25 10.13 0.73 0.44 11

5.36 0.19 0.33 0.32 12

8.08 0.3 0.59 0.34 15

>24.59 10.57 >25 9.75 16.94 18

>24.59 3.23 20.31 3.81 2.58 19

>24.59 13.31 >25 16.6 12.36 20

0.5 6.34 0.5 0.68 23

0.23 0.007 0.13 0.12 24

1.81 0.11 0.046 0.03 25

2.46 0.39 0.006 0.007 26

2.42 0.21 0.005 0.006 27

6.03 0.63 0.8 0.43 28

>25 8.77 >23.81 >23.81 29

1.58 1.66 0.82 30

12.71 0.14 0.17 0.12 31

23.23 0.51 1.3 2.2 32

6.5 0.97 1.51 0.97 33

21.66 0.98 0.81 0.52 34

>25 1.21 0.69 0.49 35

0.36 0.033 0.17 0.10 36

0.22 0.017 0.047 0.033 37

0.05 0.01 38

0.38 >25 39

0.05 0.01 40

0.03 0.01 41

0.03 0.40 42

1.73 0.45 43

0.50 0.15 44

0.10 0.04 45

0.58 1.37 46

0.21 0.03 47

14.12 1.64 48

0.01 0.01 49

0.31 0.06 50

0.03 0.01 51

0.16 0.17 52

4.42 0.41 0.42 53

3.17 0.36 0.76 54

16.1 5.65 0.05 0.07 55

4.11 0.06 1.27 1.16 57

0.44 0.06 1.21 1.38 58

0.99 0.06 2.75 2.69 60

>25 1.25 0.034 0.019 61

>25 9.73 1.34 0.95 62

21.2 >25 0.70 0.72 63

>25 2.58 6.72 4.39

All the compounds were tested in the reporter assays for assessment ofTLR8 activity and showed LEC >17 μM.

1.-5. (canceled)
 6. A method for activating TLR7 in a subject comprisingadministering to said subject an effective amount of a compound offormula (I)

or a pharmaceutically acceptable salt, solvate or polymorph thereof,wherein Y is C₁₋₄ alkylene; R₁ is selected from the group consisting ofimidazolyl, pyrimidyl, pyrrolyl, pyrazolyl, furyl, oxazolyl,oxadiazolyl, isoxazolyl, pyrazinyl and thiazolyl, wherein R₁ isoptionally substituted by one or more substituents independentlyselected from the group consisting of hydroxyl, C₁₋₆ alkyl, C₁₋₄ alkoxy,trifluoromethyl, C₃₋₆cycloalkyl, phenyl, halogen, hydroxyl-C₁₋₄ alkyl,C₁₋₄alkoxy-, C₁₋₄-alkyl- and C₁₋₄alkyl-diethoxyphosphoryl; and R₂ isaryl² or heterocyclyl.
 7. The method of claim 6, wherein the compound isselected from the group consisting of


8. A method for inducing interferon production in a subject, comprisingadministering to said subject an effective amount of a compound acompound of formula (I)

or a pharmaceutically acceptable salt, solvate or polymorph thereof,wherein Y is C₁₋₄ alkylene; R₁ is selected from the group consisting ofimidazolyl, pyrimidyl, pyrrolyl, pyrazolyl, furyl, oxazolyl,oxadiazolyl, isoxazolyl, pyrazinyl and thiazolyl, wherein R₁ isoptionally substituted by one or more substituents independentlyselected from the group consisting of hydroxyl, C₁₋₆ alkyl, C₁₋₄ alkoxy,trifluoromethyl, C₃₋₆cycloalkyl, phenyl, halogen, hydroxyl-C₁₋₄ alkyl,C₁₋₄-alkoxy-, C₁₋₄-alkyl- and C₁₋₄alkyl-diethoxyphosphoryl; and R₂ isaryl² or heterocyclyl.
 9. The method of claim 8, wherein the compound isselected from the group consisting of


10. A method of treating a viral infection in a subject comprisingadministering to said subject an effective amount of a compound offormula (I)

or a pharmaceutically acceptable salt, solvate or polymorph thereof,wherein Y is C₁₋₄ alkylene; R₁ is selected from the group consisting ofimidazolyl, pyrimidyl, pyrrolyl, pyrazolyl, furyl, oxazolyl,oxadiazolyl, isoxazolyl, pyrazinyl and thiazolyl, wherein R₁ isoptionally substituted by one or more substituents independentlyselected from the group consisting of hydroxyl, C₁₋₆ alkyl, C₁₋₄ alkoxy,trifluoromethyl, C₃₋₆cycloalkyl, phenyl, halogen, hydroxyl-C₁₋₄ alkyl,C₁₋₄alkoxy-, C₁₋₄-alkyl- and C₁₋₄alkyl-diethoxyphosphoryl; and R₂ isaryl² or heterocyclyl.
 11. The method of claim 10, wherein the compoundis selected from the group consisting of


12. A method of treating a viral infection in a subject comprisingadministering to said subject a pharmaceutical composition comprising acompound of formula (I)

or a pharmaceutically acceptable salt, solvate or polymorph thereof,wherein Y is C₁₋₄ alkylene; R₁ is selected from the group consisting ofimidazolyl, pyrimidyl, pyrrolyl, pyrazolyl, furyl, oxazolyl,oxadiazolyl, isoxazolyl, pyrazinyl and thiazolyl, wherein R₁ isoptionally substituted by one or more substituents independentlyselected from the group consisting of hydroxyl, C₁₋₆ alkyl, C₁₋₄ alkoxy,trifluoromethyl, C₃₋₆cycloalkyl, phenyl, halogen, hydroxyl-C₁₋₄ alkyl,C₁₋₄alkoxy-, C₁₋₄-alkyl- and C₁₋₄alkyl-diethoxyphosphoryl; R₂ is aryl²or heterocyclyl; and one or more pharmaceutically acceptable excipients,diluents or carriers.
 13. The method of claim 12, wherein the compoundis selected from the group consisting of